scholarly journals Epigenetic Alterations Induced by Photothrombotic Stroke in the Rat Cerebral Cortex: Deacetylation of Histone h3, Upregulation of Histone Deacetylases and Histone Acetyltransferases

2019 ◽  
Vol 20 (12) ◽  
pp. 2882 ◽  
Author(s):  
Svetlana Demyanenko ◽  
Anatoly Uzdensky
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Histone Deacetylases ◽  
Protein Biosynthesis ◽  
Histone H3 ◽  
Histone Acetyltransferases ◽  
Ischemic Penumbra ◽  
Cell Nuclei ◽  
Vessel Occlusion ◽  
Photothrombotic Stroke

Ischemic penumbra that surrounds a stroke-induced infarction core is potentially salvageable; however, mechanisms of its formation are not well known. Covalent modifications of histones control chromatin conformation, gene expression and protein synthesis. To study epigenetic processes in ischemic penumbra, we used photothrombotic stroke (PTS), a stroke model in which laser irradiation of the rat brain cortex photosensitized by Rose Bengal induces local vessel occlusion. Immunoblotting and immunofluorescence microscopy showed decrease in acetylation of lysine 9 in histone H3 in penumbra at 1, 4 or 24 h after PTS. This was associated with upregulation of histone deacetylases HDAC1 and HDAC2, but not HDAC4, which did not localize in the nuclei. HDAC2 was found in cell nuclei, HDAC4 in the cytoplasm and HDAC1 both in nuclei and cytoplasm. Histone acetyltransferases HAT1 and PCAF (p300/CBP associated factor) that acetylated histone H3 synthesis were also upregulated, but lesser and later. PTS increased localization of HDAC2 and HAT1 in astroglia. Thus, the cell fate in PTS-induced penumbra is determined by the balance between opposite tendencies leading either to histone acetylation and stimulation of gene expression, or to deacetylation and suppression of transcriptional processes and protein biosynthesis. These epigenetic proteins may be the potential targets for anti-stroke therapy.

scholarly journals Reduced Histone H3 Acetylation in CD4+T Lymphocytes: Potential Mechanism of Latent Autoimmune Diabetes in Adults

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Xi-yu Liu ◽  
Jiang-feng Xu
Keyword(s):  
Gene Expression ◽  
T Lymphocytes ◽  
Histone Deacetylases ◽  
Autoimmune Diabetes ◽  
Histone H3 ◽  
Histone Acetyltransferases ◽  
Healthy Controls ◽  
Latent Autoimmune Diabetes ◽  
Histone H3 Acetylation ◽  
H3 Acetylation

Aims. Latent autoimmune diabetes in adults (LADA) is the result of gene-environment interactions. Histone acetylation regulates gene expression and maybe interpret how environmental factors modify LADA. Hence, we studied the histone acetylation patterns in CD4+T lymphocytes from LADA patients.Methods. Blood CD4+T lymphocytes from 28 patients with LADA and 28 healthy controls were obtained to detect histone H3 acetylation and H4 acetylation. The gene expression of histone acetyltransferases (P300 and CREBBP) and histone deacetylases (HDAC1, HDAC2, and HDAC7) was measured by real-time polymerase chain reaction (RT-PCR).Results. Compared to healthy controls, reduced global H3 acetylation was observed in LADA patients’ CD4+T lymphocytes (P<0.05). Global level of H4 acetylation was not statistically different. Among LADA, CD4+T lymphocytes H3 acetylation was associated with glycosylated hemoglobin (HbA1c) and GADA titer. Compared to healthy controls, the expression of histone acetyltransferases CREBBP in LADA patients was downregulated, and the expression of histone deacetylases HDAC1 and HDAC7 was upregulated.Conclusion. A concerted downregulation of histone H3 acetylation was found in CD4+T lymphocytes of LADA patients, and this might provide evidence of a novel epigenetic explanation for the pathogenesis of LADA and its complications.

scholarly journals In Vitro Targeting Reveals Intrinsic Histone Tail Specificity of the Sin3/Histone Deacetylase and N-CoR/SMRT Corepressor Complexes

2004 ◽  
Vol 24 (6) ◽  
pp. 2364-2372 ◽  
Author(s):  
Michiel Vermeulen ◽  
Michael J. Carrozza ◽  
Edwin Lasonder ◽  
Jerry L. Workman ◽  
Colin Logie ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Chromatin Structure ◽  
Histone Deacetylases ◽  
Histone H3 ◽  
Histone Code ◽  
Histone Acetyltransferases ◽  
Histone Tail ◽  
In Vitro System ◽  
Selective Targeting

ABSTRACT The histone code is among others established via differential acetylation catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). To unambiguously determine the histone tail specificity of HDAC-containing complexes, we have established an in vitro system consisting of nucleosomal templates reconstituted with hyperacetylated histones or recombinant histones followed by acetylation with native SAGA or NuA4. Selective targeting of the mammalian Sin3/HDAC and N-CoR/SMRT corepressor complexes by using specific chimeric repressors created a near physiological setting to assess their histone tail specificity. Recruitment of the Sin3/HDAC complex to nucleosomal templates preacetylated with SAGA or NuA4 resulted in deacetylation of histones H3 and H4, whereas recruitment of N-CoR/SMRT resulted in deacetylation of histone H3 only. These results provide solid evidence that HDAC-containing complexes display distinct, intrinsic histone tail specificities and hence may function differently to regulate chromatin structure and transcription.

scholarly journals SUMOylation of the chromodomain factor MRG-1 in C. elegans affects chromatin-regulatory dynamics

2021 ◽  
Author(s):  
Gülkiz Baytek ◽  
Alexander Blume ◽  
Funda Gerceker Demirel ◽  
Selman Bulut ◽  
Philipp Mertins ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Protein Interaction ◽  
Interaction Analysis ◽  
Mammalian Species ◽  
Strong Association ◽  
Histone H3 ◽  
C Elegans ◽  
Protein Protein Interaction ◽  
Lysine Residues

AbstractEpigenetic mechanisms to control chromatin accessibility and structure is important for gene expression in eukaryotic cells. Chromatin regulation ensures proper development and cell fate specification but is also essential later in life. Modifications of histone proteins as an integral component of chromatin can promote either gene expression or repression, respectively. Proteins containing specific domains such as the chromodomain recognize mono-, di- or tri-methylated lysine residues on histone H3. The chromodomain protein MRG-1 in Caenorhabditis elegans is the ortholog of mammalian MRG15, which belongs to the MORF4 Related Gene (MRG) family in humans. In C. elegans MRG-1 predominantly binds methylated histone H3 lysine residues at position 36 (H3K36me3). MRG-1 is important during germline maturation and for safeguarding the germ cell identity. However, it lacks enzymatic activity and depends on protein-protein interaction to cooperate with other factors to regulate chromatin. To elucidate the variety of MRG-1 interaction partners we performed in-depth protein-protein interaction analysis using immunoprecipitations coupled with mass-spectrometry. Besides previously described and novel interactions with other proteins, we also detected a strong association with the Small Ubiquitin-like Modifier (SUMO). Since SUMO is known to be attached to proteins in order to modulate the target proteins activity we assessed whether MRG-1 is post-translationally modified by SUMOylation. Notably, we provide evidence that MRG-1 is indeed SUMOylated and that this post-translational modification influences the chromatin-binding profile of MRG-1 in the C. elegans genome. Our presented study hints towards an important role of SUMOylation in the context of epigenetic regulation via the chromodomain protein MRG-1, which may be a conserved phenomenon also in mammalian species.

The emerging role of class II histone deacetylases

2001 ◽  
Vol 79 (3) ◽  
pp. 337-348 ◽  
Author(s):  
Wolfgang Fischle ◽  
Veronique Kiermer ◽  
Franck Dequiedt ◽  
Eric Verdin
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Histone Deacetylases ◽  
Class Ii ◽  
Histone Acetyltransferases ◽  
Class Iii ◽  
Nucleocytoplasmic Shuttling ◽  
Class I Hdacs ◽  
Shed Light

Histone acetylation and deacetylation play essential roles in modifying chromatin structure and regulating gene expression in all eukaryotes. Several histone acetyltransferases have been identified that act as transcriptional coactivators. In contrast, histone deacetylases (HDACs) are part of transcriptional corepressor complexes. Based on their similarity to known yeast factors, the human HDACs are grouped into three classes. Class I HDACs are similar to the yeast transcriptional repressor yRPD3, while class II HDACs are related to yHDA1 and class III HDACs to ySIR2. In this review, we focus on the biology of class II HDACs. These newly discovered enzymes have been implicated in cell differentiation and development, and many molecular details are emerging that shed light on class II HDAC function and regulation. We discuss the biological role of these factors in the context of physiological processes.Key words: transcriptional regulation, histone deacetylases, class II HDACs, nucleocytoplasmic shuttling, MEF2.

Human neuronal cells: epigenetic aspects

2013 ◽  
Vol 4 (4) ◽  
pp. 319-333 ◽  
Author(s):  
Jessica Kukucka ◽  
Tessa Wyllie ◽  
Justin Read ◽  
Lauren Mahoney ◽  
Cenk Suphioglu
Keyword(s):  
Gene Expression ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Posttranslational Modifications ◽  
Histone Deacetylases ◽  
Neuronal Cells ◽  
Hdac Inhibitors ◽  
Histone Acetyltransferases ◽  
Human Neuronal Cells ◽  
The Brain

AbstractHistone acetyltransferases (HATs) and histone deacetylases (HDACs) promote histone posttranslational modifications, which lead to an epigenetic alteration in gene expression. Aberrant regulation of HATs and HDACs in neuronal cells results in pathological consequences such as neurodegeneration. Alzheimer’s disease is the most common neurodegenerative disease of the brain, which has devastating effects on patients and loved ones. The use of pan-HDAC inhibitors has shown great therapeutic promise in ameliorating neurodegenerative ailments. Recent evidence has emerged suggesting that certain deacetylases mediate neurotoxicity, whereas others provide neuroprotection. Therefore, the inhibition of certain isoforms to alleviate neurodegenerative manifestations has now become the focus of studies. In this review, we aimed to discuss and summarize some of the most recent and promising findings of HAT and HDAC functions in neurodegenerative diseases.

scholarly journals The C Terminus of p53 Family Proteins Is a Cell Fate Determinant

2005 ◽  
Vol 25 (5) ◽  
pp. 2014-2030 ◽  
Author(s):  
Kelly Lynn Harms ◽  
Xinbin Chen
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Histone Deacetylases ◽  
Target Gene ◽  
Combined Treatment ◽  
Full Length ◽  
Activation Domain ◽  
P53 Family ◽  
Basic Domain

ABSTRACT The p53 tumor suppressor is the most commonly mutated gene in human cancers. The ability of p53 to induce cell cycle arrest, apoptosis, DNA repair, and other p53-dependent activities is well known; however, the mechanism by which p53 induces a specific activity over another is unclear. Here, we showed that stringent regulation of and by p53 family isoforms facilitates differential target gene expression and thus determines cell fate. Through the use of engineered deletion mutants, we found that activation domain 2 is required for induction of the proapoptotic target gene insulin-like growth factor binding protein 3 (IGFBP3) by p53 and that the basic domain inhibits induction of this gene by p53. Thus, for the first time we provide evidence that the basic domain of p53 is inhibitory in vivo as has been determined in vitro. We also showed that the in vivo inhibitory activity of the basic domain depends upon activation domain 1, such that combined deletion of activation domain 1 and the basic domain was required to alleviate the inhibition by the basic domain. Importantly, deletion of the inhibitory functional domains, namely N-terminal activation domain 1 and the C-terminal basic domain, is paralleled in nature. We found that the IGFBP3 promoter was activated by p53(ΔNΔBD), which mimics a naturally occurring N- and C-terminally truncated human p53 isoform, and by p53AS, a C-terminally truncated murine p53 isoform generated through alternative splicing, but not by full-length human or murine p53. In addition, we found that the C termini of p63 and p73 inhibit the induction of IGFBP3, such that C-terminally truncated p63 and p73 isoforms induce the expression of IGFBP3, whereas full-length ones cannot. We also demonstrated that IGFBP3 is an important effector of the apoptosis induced by N- and C-terminally truncated p53, such that knockdown of IGFBP3 by using an IGFBP3 neutralizing antibody or IGFBP3 small interfering RNA partially rescues the cell death induced by N- and C-terminally truncated p53. In addition, we identified that histone deacetylase activity, not p53 DNA binding ability, governs the regulation of IGFBP3 by full-length p53 family proteins, as inhibition of histone deacetylases restores the induction of IGFBP3 by exogenous full-length p53, p63, and p73 proteins. Furthermore, we found that activation of p53 or inhibition of histone deacetylases alone was not sufficient to induce IGFBP3; however, combined treatment endowed endogenous p53 with this activity. To better understand the significance of this regulation, we performed a microarray study and identified several target genes differentially regulated by full-length p53 and p53 lacking the N-terminal activation domain 1 and the C-terminal basic domain. Taken together, our data suggest a novel mechanism by which p53 family proteins differentially regulate gene expression and provide an insight for designing a combined therapy for cancer treatment.

scholarly journals Transcription levels of a long noncoding RNA orchestrate opposing regulatory and cell fate outcomes in yeast

2019 ◽  
Author(s):  
Fabien Moretto ◽  
N. Ezgi Wood ◽  
Minghao Chia ◽  
Cai Li ◽  
Nicholas M. Luscombe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Fate ◽  
Transcriptional Repression ◽  
Noncoding Rna ◽  
Histone H3 ◽  
Noncoding Rnas ◽  
Enhancer Rna ◽  
Regulatory Circuit ◽  
In Cis ◽  
Histone Exchange

ABSTRACTMany long noncoding RNAs (lncRNAs) act in cis through transcription-coupled chromatin alterations that drive changes in local gene expression. How some cis-acting lncRNAs promote and others repress gene expression remains poorly understood. Here we report that in S. cerevisiae transcription levels of the lncRNA IRT2, located upstream in the promoter of the inducer of meiosis gene, regulate opposing chromatin and transcription states. Low IRT2 transcription displays enhancer RNA-like features. At these levels, IRT2 promotes histone exchange delivering acetylated histone H3 lysine 56 to chromatin thereby facilitating recruitment of a transcription factor and consequently activating transcription. Conversely, increasing IRT2 transcription enhances chromatin assembly and transcriptional repression. The opposing functions of IRT2 direct a regulatory circuit, which ensures that cells expressing opposite, but not one of either, mating-type loci enter meiosis. Our data demonstrate that the transcription levels of an lncRNA are key to controlling gene expression and cell fate outcomes.

scholarly journals POWERDRESS and HDA9 interact and promote histone H3 deacetylation at specific genomic sites inArabidopsis

2016 ◽  
Vol 113 (51) ◽  
pp. 14858-14863 ◽  
Author(s):  
Yun Ju Kim ◽  
Ruozhong Wang ◽  
Lei Gao ◽  
Dongming Li ◽  
Chi Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Specific Binding ◽  
Expression Profiles ◽  
Histone H3 ◽  
Gene Expression Profiles ◽  
Large Gene ◽  
Lysine Residues

Histone acetylation is a major epigenetic control mechanism that is tightly linked to the promotion of gene expression. Histone acetylation levels are balanced through the opposing activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs).ArabidopsisHDAC genes (AtHDACs) compose a large gene family, and distinct phenotypes amongAtHDACmutants reflect the functional specificity of individualAtHDACs. However, the mechanisms underlying this functional diversity are largely unknown. Here, we show that POWERDRESS (PWR), a SANT (SWI3/DAD2/N-CoR/TFIII-B) domain protein, interacts with HDA9 and promotes histone H3 deacetylation, possibly by facilitating HDA9 function at target regions. The developmental phenotypes ofpwrandhda9mutants were highly similar. Three lysine residues (K9, K14, and K27) of H3 retained hyperacetylation status in bothpwrandhda9mutants. Genome-wide H3K9 and H3K14 acetylation profiling revealed elevated acetylation at largely overlapping sets of target genes in the two mutants. Highly similar gene-expression profiles in the two mutants correlated with the histone H3 acetylation status in thepwrandhda9mutants. In addition,PWRandHDA9modulated flowering time by repressingAGAMOUS-LIKE 19expression through histone H3 deacetylation in the same genetic pathway. Finally, PWR was shown to physically interact with HDA9, and its SANT2 domain, which is homologous to that of subunits in animal HDAC complexes, showed specific binding affinity to acetylated histone H3. We therefore propose that PWR acts as a subunit in a complex with HDA9 to result in lysine deacetylation of histone H3 at specific genomic targets.

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